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Cell Rep. 2016 Jun 14;15(11):2475-87. doi: 10.1016/j.celrep.2016.05.020. Epub 2016 Jun 2.

Two Mutually Exclusive Local Chromatin States Drive Efficient V(D)J Recombination.

Author information

1
Nuclear Dynamics Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
2
Bioinformatics Group, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
3
Nuclear Dynamics Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK. Electronic address: mikhail.spivakov@babraham.ac.uk.
4
Nuclear Dynamics Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK. Electronic address: anne.corcoran@babraham.ac.uk.

Abstract

Variable (V), diversity (D), and joining (J) (V(D)J) recombination is the first determinant of antigen receptor diversity. Understanding how recombination is regulated requires a comprehensive, unbiased readout of V gene usage. We have developed VDJ sequencing (VDJ-seq), a DNA-based next-generation-sequencing technique that quantitatively profiles recombination products. We reveal a 200-fold range of recombination efficiency among recombining V genes in the primary mouse Igh repertoire. We used machine learning to integrate these data with local chromatin profiles to identify combinatorial patterns of epigenetic features that associate with active VH gene recombination. These features localize downstream of VH genes and are excised by recombination, revealing a class of cis-regulatory element that governs recombination, distinct from expression. We detect two mutually exclusive chromatin signatures at these elements, characterized by CTCF/RAD21 and PAX5/IRF4, which segregate with the evolutionary history of associated VH genes. Thus, local chromatin signatures downstream of VH genes provide an essential layer of regulation that determines recombination efficiency.

PMID:
27264181
PMCID:
PMC4914699
DOI:
10.1016/j.celrep.2016.05.020
[Indexed for MEDLINE]
Free PMC Article

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